The present invention generally relates to powder flow testing and analysis. More specifically, the present invention relates to a method for predicting the flow properties of powders based on a ranking of data derived from one or more powder flow tests.
In many processes or systems involving powder materials, especially pharmaceutical manufacturing processes, the material being processed must possess good flow properties in order for the manufacturing process to be successful. In the case of pharmaceutical processes, the material generally constitutes a formulation or blend of active ingredients as well as excipients. The excipients are usually inert substances (e.g., gum arabic, starch and the like) which serve as a vehicle for the active ingredients, or as lubricants, glidants, and bulking components. Poor flow characteristics of such formulations can result in equipment stoppages, clogged outlets, flooded compartments, and other conditions that disrupt the flow of the material during processing. One example of an important pharmaceutical process in which good flow properties are critical is the compression of powders into tablets that require uniform, consistent dosages and compositions. Powder compression can involve known process steps such as funneling, avalanching, tumbling, plug drop and the like.
The widespread use of powders in the pharmaceutical industry has given rise to a variety of methods for characterizing powder flow. Much research has been directed toward attempting to correlate the various measures of powder flow to manufacturing properties. It is believed that the multitude of test methods developed thus far is a result of the fact that powder flow behavior is multifaceted and complex. The pharmaceutical scientist often utilizes one or more of the standard tests to assess the flowability potential of sample powder materials and formulations. For a given manufacturing process and a given active drug substance or compound, such tests are employed to evaluate the optimal blend of active ingredients and excipients constituting the bulk quantity to be processed. It is well documented that the various flow tests generally accepted and commonly employed to date often do not correlate well with observed behavior on a development or production scale. One reason is that none of the tests reflect an intrinsic property of the powder being tested. In other words, each test is strongly dependent upon its respective methodology. There is a growing awareness, therefore, that because powder flow in general is a complex phenomenon, no single, simple test method can adequately characterize the wide range of flow properties observed for pharmaceutical powders.
Examples of basic, conventional flow tests are as follows. One popular test is the static angle of repose test. This test measures the xe2x80x9cangle of repose,xe2x80x9d which can be defined as the constant, three-dimensional angle relative to a horizontal base that is assumed by a cone-like pile of material formed by any of several different methods. A lower angle of repose value indicates better powder flow. The angle of repose is formed by permitting powder to drop through a funnel onto a fixed, vibration-free base that includes a retaining lip to retain a layer of powder on the base. The height of the funnel is varied during the test in order to carefully build up a symmetrical cone of powder. Typically, the funnel height is maintained approximately 2 to 4 cm from the top of the powder pile as it is being formed in order to minimize the impact of falling powder on the tip of the cone. Alternatively, the funnel could be kept fixed while the base is permitted to vary as the pile forms. The angle of repose is determined by measuring the height of the powder cone and calculating the angle of repose ∀ from the following equation:       tan    ⁡          (      α      )        =      height                  1        /        2            ⁢              xe2x80x83            ⁢      base      
One variation of this test is the drained angle of repose test, wherein an excess quantity of material positioned above a fixed diameter base is allowed to xe2x80x9cdrainxe2x80x9d from the container. The drained angle of repose is determined from the cone of powder formed on the base. Another variation is the dynamic angle of repose test, in which a cylinder is filled and rotated at a specified speed. The dynamic angle of repose is the angle formed by the flowing powder.
It is believed that the angle of repose is essentially a measure of interparticulate friction, or resistance to movement between particles. Experimental difficulties arise in the use of this test due to segregation of material and consolidation or aeration of the powder as the cone is formed. Also, the peak of the cone of powder can be distorted by the impact of the powder falling from above, although this can be minimized somewhat by carefully building up the cone. In addition, the design of the base upon which the cone is formed influences the angle of repose. The provision of a fixed diameter base having a protruding outer edge can ameliorate this latter influence by ensuring that the cone of powder is formed on a retained layer of powder. Of course, if a powder of a given formulation is not capable of forming a symmetrical cone, this test is entirely inappropriate. Thus, although widely accepted as being valuable in predicting manufacturing problems, the angle of repose test has nonetheless been criticized on the grounds of lack of reproducibility and inconsistency in its ability to correlate with manufacturing properties or other measures of powder flow.
Another popular test for predicting powder flow characteristics measures the compressibility index or the closely related Hausner ratio. The test involves measuring the bulk or aerated density Va of a powder in a graduated cylinder, placing the cylinder on a tap density tester such as a Vanderkamp TAP DENSITY TESTER(trademark), and measuring the xe2x80x9ctappedxe2x80x9d density Vf of the powder, i.e., the density of the powder after tapping the cylinder a number of times (e.g., 200) until no further volumetric changes occur. A lower compressibility index value indicates better powder flow. One of the following calculations is then made:                               compressibility          ⁢                      xe2x80x83                    ⁢          index                =                  100          xc3x97                      (                                                            V                  a                                -                                  V                  f                                                            V                a                                      )                                                            Hausner          ⁢                      xe2x80x83                    ⁢          ratio                =                              V            a                                V            f                              
The values obtained as a result of this test are believed to be measures of the cohesiveness of a powder as it forms an arch in a hopper and the ease with which such an arch could be broken. In one variation, the rate of consolidation is also, or alternatively, measured. Factors influencing the methods used to obtain the compressibility index and the Hausner ratio include the diameter of the cylinder used, the number of times the powder is tapped to achieve the tapped density, the mass of material used in the test, and rotation of the sample during tapping.
Another type of test entails monitoring the rate of flow and/or change in flow rate of a powdered material through an orifice in order to obtain a measure of flowability and an indication of the effects of glidants, granule size and type of granulating agent on powder flow. The xe2x80x9cflow through the orificexe2x80x9d test is useful only for free-flowing, non-cohesive materials. Either mass flow rate or volumetric flow rate can be measured, and done so either continuously or discretely. It is generally recommended that the container employed for this test be a vibration-free cylinder with a circular orifice. The size and shape of the container and orifice are important experimental variables. The diameter of the cylinder is recommended to be greater that two times the diameter of the orifice, while the diameter of the orifice is recommended to be greater than six times the diameter of the particles to be tested. A hopper could also serve as the container where representative of flow in a manufacturing situation. A funnel is not recommended since its stem would affect the flow rate. The test might involve the use of empirical equations that relate flow rate to the orifice diameter, particle size, and particle density.
A diverse array of shear cell methods have also been developed, and are considered to offer a greater degree of experimental control and provide a large amount of useful flow data. The parameters generated include the yield loci representative of shear stress-shear strain relationship, the angle of internal friction, the unconfined yield strength, and the tensile strength, as well as derived parameters such as the flow factor. In a typical shear cell test, a cylindrical shear cell is split horizontally to form a shear plane between a lower stationary base and the upper moveable portion of a shear cell ring. After powder bed consolidation in the shear cell, the force necessary to shear the powder bed by moving the upper ring is determined. Variations include annular and plate-type shear cell designs.
Another test involves avalanching methods, for which an Amherst Process Instruments AERO-FLOW(trademark) device can be employed. Approximately 20 grams of material are loaded into a translucent drum, and the drum is rotated slowly at the rate of 120 seconds per revolution. A photocell array detector measures the total number of avalanches, and the average time between avalanches is calculated. A lower average time between avalanches indicates better powder flow.
A further test involves the use of a vibrating spatula or trough, such as a Hierath Automated Systems ISO-G4107, which cascades powder onto a mass balance interfacing with the vibrating spatula. Approximately 100 mL of powder is placed behind a removable gate 3 inches from the rear of the spatula and the vibration amplitude is set at 40%. The gate is removed and the mass of accumulated powder is recorded at 10-second intervals. Steeper slopes of mass accumulated vs. time plots represent better powder flow.
Finally, several variations of each of these basic methods described in detail hereinabove have been developed.
While attempts have been made to standardize and improve the various test methodologies, there remains a long-felt need for developing a method for accurately predicting the flow properties that powders can be expected to exhibit when processed in a given system.
The present invention provides a novel approach to assessing the flow properties of powders such as pharmaceutical materials. A fundamental principle of the present invention is a recognition that, not only is powder flow difficult to analyze with just one flow test or even a combination of flow tests, but accurate prediction of powder flow must take into account the different types of flow occurring in a given process or system at certain steps, or key points, of the process or system. The present invention accounts for these different flow types, and models each key point or system step by conducting a test that replicates the flow type observed at that particular key point. The specific test utilized for the corresponding key point can be a conventional test or any new test yet to be developed. A test is conducted for each flow point and for each candidate powder formulation under inquiry. After conducting each test on each proposed formulation, a ranking of the different formulations is determined. To enhance the utility of the present invention, the ranking can be based on a weighted average of the test results. Thus, the weighting factor used for a particular test result can be made equal or skewed, depending on the relative importance of each key point within the context of the overall system. As a result of the inventive method, one of the candidate powder formulations is identified as possessing the most promising flow properties for the particular system in which the powder is to be processed.
Preliminary studies have shown that the present inventive approach provides a superior and highly relevant prediction of flow during the compression of tablets, as compared to the mere use of one or more conventional tests to model an entire system.
According to one aspect of the present invention, a method is provided for predicting flow properties of one or more materials, in a case where such materials are proposed for processing in a system which requires good flow properties in order to operate successfully. The method comprises identifying a plurality of key flow points along the system and for each key flow point, characterizing the type of flow occurring at that key flow point and selecting a flow test relevant for modeling the type of flow occurring at that key flow point. A plurality of material samples are provided wherein each material sample has a different composition, blend or concentration of ingredients. For each key flow point, the type of flow occurring at that key flow point is modeled by conducting the flow test selected for that key flow point on each material sample to produce a plurality of test result values. Each test result value is a function of one of the flow tests conducted and of the material sample tested by that flow test. Each material sample is ranked based on a calculated average of the test result values to determine which of the material samples tested has optimal overall flow properties for the system as compared against the other material samples.
The test result values for each flow test conducted can be normalized by adjusting the test result value having the best ranking by a factor that sets that test result value to unity, and adjusting the other test result values obtained from that flow test by the same factor to convert the other test result values to reduced values equal to less than unity.
A weighting factor can be assigned to the test result value produced by each flow test conducted. The weighting factor is based on an assessed significance of the key flow point modeled by that flow test relative to the other key flow points identified for the system, such that the step of ranking each material sample is based on a weighted average of the test result values.
According to another aspect of the present invention, a method is provided for predicting flow properties of one or more materials wherein an overall ranking each of material sample is generated to predict the flow properties that each material sample will exhibit during processing of the material sample in the system. The following equation can be utilized:
overall rank for powder (X)=[Test #1 scorexc3x97(1/N)xc3x97WF1]++[Test #N scorexc3x97(1/N)xc3x97WFN],
wherein (X) designates one of the material samples tested; xe2x80x9cNxe2x80x9d represents the total number of flow tests conducted; xe2x80x9cTest #1 scorexe2x80x9d is the test result value obtained from conducting a first one of the plurality of flow tests corresponding to a first one of the key flow points identified; xe2x80x9cWF1xe2x80x9d is a weighting factor optionally assigned to the Test #1 score based on an assessed significance of the first key flow point relative to the other key flow points; xe2x80x9cTest #N scorexe2x80x9d is the test result value obtained from conducting an Nth one of the plurality of flow tests corresponding to an Nth one of the key flow points identified; and xe2x80x9cWFNxe2x80x9d is a weighting factor optionally assigned to the Test #N score based on an assessed significance of the Nth key flow point relative to the other key flow points.
According to yet another aspect of the present invention, a method is provided for predicting flow properties of one or more powder formulations proposed for processing in a system which requires good powder flow properties to operate successfully. The method includes identifying a plurality of key powder flow points along a system. For each key flow point, the type of flow occurring at that key flow point is characterized and a powder flow test relevant for modeling the type of flow occurring at that key flow point is selected. A plurality of powder samples are provided wherein each powder sample has a different composition, blend or concentration of ingredients. For each key flow point and for each powder sample, the type of flow occurring at that key flow point is modeled by conducting the powder flow test selected for that key flow point to produce a plurality of test result values. Each test result value is a function of one of the powder flow tests conducted and of the powder sample tested by that powder flow test. Each powder sample is ranked based on a calculated average of the test result values to determine which of the powder samples tested has optimal overall flow properties for the system as compared against the other powder samples.
The system under inquiry can include a tablet forming system including a hopper, a funnel fluidly communicating with the hopper, a feed frame fluidly communicating with the funnel, and a die table fluidly communicating with the feed frame.
According to a further aspect of the present invention, a pharmaceutical product is formed from a powder formulation predicted to exhibit optimized powder flow in a pharmaceutical product manufacturing system. The optimized powder formulation is determined by one of the ranking processes as described and claimed herein.
It is therefore an object of the present invention to provide a method for predicting the flow properties of one or more powders in a given system with a greater degree of accuracy, relevancy and validity than heretofore accomplished.
It is another object of the present invention to provide a method for predicting the flow properties of powders which produces a ranking of powders for use in selecting a candidate powder formulation for further development.